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Chronic kidney disease progression in IgA nephropathy

ABSTRACT: Palmitoylation, a vital post-translational modification of proteins, has remained largely unexplored in immune-associated kidney diseases. This study is the first to reveal that palmitoylation plays a pivotal role in IgA nephropathy (IgAN) by regulating the activity of the transcription factor TEA Domain Transcription Factor 4 (TEAD4), thereby driving Th17 cell recruitment. Moreover, our findings suggest that inhibiting palmitoylation could act as a "braking" mechanism to slow disease progression. By analyzing clinical samples from IgAN patients and mouse models, we observed a significant positive correlation between the extent of Th17 cell infiltration in renal tissues and disease severity. Mechanistic investigations demonstrated that, under an inflammatory microenvironment, damaged renal tubular epithelial cells upregulate the expression of the chemokine CCL20 via TEAD4, thereby promoting Th17 cell recruitment. Notably, we identified that TEAD4 activity is regulated by its palmitoylation status, rather than changes in its protein expression levels. Further analysis identified zinc finger DHHC-type palmitoyltransferase 14 (ZDHHC14) as the critical enzyme mediating TEAD4 palmitoylation. ZDHHC14 was found to be highly expressed in the renal tissues of both IgAN patients and mouse models. Knockdown of ZDHHC14 significantly reduced CCL20 expression and diminished Th17 cell infiltration. In vivo therapeutic experiments confirmed that the ZDHHC inhibitor 2-bromopalmitate (2-BP) effectively alleviated Th17 cell infiltration and renal interstitial fibrosis, substantially delaying disease progression in IgAN mice. This study provides the first comprehensive insight into the regulatory mechanism of TEAD4 palmitoylation in IgAN progression. It further proposes a novel therapeutic approach targeting palmitoylation to modulate Th17 cell recruitment, offering critical theoretical foundations and potential clinical applications for the precise treatment of immune-mediated kidney diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE287962 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description:Palmitoylation, a vital post-translational modification of proteins, has remained largely unexplored in immune-associated kidney diseases. This study is the first to reveal that palmitoylation plays a pivotal role in IgA nephropathy (IgAN) by regulating the activity of the transcription factor TEA Domain Transcription Factor 4 (TEAD4), thereby driving Th17 cell recruitment. Moreover, our findings suggest that inhibiting palmitoylation could act as a "braking" mechanism to slow disease progression. By analyzing clinical samples from IgAN patients and mouse models, we observed a significant positive correlation between the extent of Th17 cell infiltration in renal tissues and disease severity. Mechanistic investigations demonstrated that, under an inflammatory microenvironment, damaged renal tubular epithelial cells upregulate the expression of the chemokine CCL20 via TEAD4, thereby promoting Th17 cell recruitment. Notably, we identified that TEAD4 activity is regulated by its palmitoylation status, rather than changes in its protein expression levels. Further analysis identified zinc finger DHHC-type palmitoyltransferase 14 (ZDHHC14) as the critical enzyme mediating TEAD4 palmitoylation. ZDHHC14 was found to be highly expressed in the renal tissues of both IgAN patients and mouse models. Knockdown of ZDHHC14 significantly reduced CCL20 expression and diminished Th17 cell infiltration. In vivo therapeutic experiments confirmed that the ZDHHC inhibitor 2-bromopalmitate (2-BP) effectively alleviated Th17 cell infiltration and renal interstitial fibrosis, substantially delaying disease progression in IgAN mice. This study provides the first comprehensive insight into the regulatory mechanism of TEAD4 palmitoylation in IgAN progression. It further proposes a novel therapeutic approach targeting palmitoylation to modulate Th17 cell recruitment, offering critical theoretical foundations and potential clinical applications for the precise treatment of immune-mediated kidney diseases.

Project description:Immunoglobulin A Nephropathy (IgAN) is a complex multifactorial disease whose genetic bases remain unknown. Distinct linkage and genome-wide association studies in both familial and sporadic IgAN suggest that there is a strong genetic component in IgAN. In this context, an intriguing role could be ascribed to copy number variants (CNVs) that have been recognized as an important source of genetic variation in humans. Here, we performed a whole-genome screening of CNVs in IgAN patients, their healthy relatives and healthy subjects (HS). A total of 217 individuals consisting of 51 IgAN cases and 166 healthy relatives were included in the initial screening. The high-throughput analysis of structural genetic variations, to find concordant aberrations across classes of samples, identified 178 IgAN-specific aberrations, specifically 114 loss and 64 gain. Several CNVs overlapped with regions evidenced by previous genome-wide genetic studies. Moreover, we found that IgAN patients characterized by deteriorated renal function carried low copy numbers of a CNV in chromosome 3 (chr3_loss:52031010-52260722). This CNV contained the TLR9 gene whose expression significantly correlated with the loss aberration in patients with progressive renal damage. Conversely, IgAN patients with normal renal function had no chr3_loss:52031010-52260722 and the TLR9 mRNA was expressed at the same level as in HS, still maintaining a strong correlation with the CNV. In conclusion, here we performed the first genome-wide CNV study in IgAN identifying some structural variants specific to IgAN patients and providing a collection of new candidate genes and loci that could help to dissect the complex genomic setting of the disease. Moreover, we identified a specific CNV, spanning the TLR9 gene, which could explain the disease severity in IgAN patients. To perform a genome-wide CNV study in IgAN identifying some structural variants specific to IgAN patients and providing a collection of new candidate genes and loci that could help to dissect the complex genomic setting of the disease.

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Chronic kidney disease progression in IgA nephropathy

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